Abstract

Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascu- lar disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the “balance” of pro-oxidants and antioxidants can- not be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thiore- doxin-1 (-SH2/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxi- cants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. Thus, from a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control. Adoption of such a definition could redirect research to identify key perturbations of redox signaling and control and lead to new treatments for oxidative stress-related disease processes. Antioxid. Redox Signal. 8, 1865–1879.